Agents that activate muscarinic acetylcholine receptors (mAChRs) have exciting potential as novel treatments for improving cognitive function in patients suffering from multiple CNS disorders, including schizophrenia, Alzheimer?s disease (AD), and other neurodegenerative disorders. Previous mAChR agonists failed in clinical development due to a lack of selectivity for individual mAChR subtypes and adverse effects associated with activation of peripheral mAChRs. We have now discovered and characterized highly selective positive allosteric modulators (PAMs) for individual mAChR subtypes and found that selective PAMs for the M1 subtype robust cognition-enhancing effects in rodents. In the parent grant associated with this supplement application, we focus on effects of these novel M1 PAMs on pathophysiological changes in brain circuits that are relevant for schizophrenia. However, abundant clinical and preclinical evidence suggests that M1 PAMs may also reduce cognitive impairments in patients suffering from AD. This possibility is especially exciting in the context of our recent success in advancing a highly selective M1 PAM into clinical development, and our finding that this compound does not induce cholinergic adverse effects at doses and exposure levels that are in large excess of those required to achieve cognition-enhancing effects. However, the major focus of our work has been on treatment of cognitive disturbances in schizophrenia patients and these compounds have not been evaluated in animal models that are relevant for AD. It will now be critical to fully evaluate selective M1 PAMs in our series in animal models for treatment of AD and other neurodegenerative disorders. If successful, this would provide strong preclinical support for evaluating these novel M1 PAMs in patients suffering from AD. We now propose a highly targeted series of studies in which we will leverage the tremendous advances made using funding by the parent grant and other funding sources by evaluating the efficacy of M1 PAMs in reversing deficits in hippocampal synaptic plasticity and cognitive function in CKp25 mice, a rodent model that induces severe neuropathological changes that are strikingly similar to those observed in AD patients (decreased brain mass, increased tau phosphorylation/aggregation, neurofibrillary tangles, and elevated A?), along with striking impairments in synaptic plasticity and cognitive function. Completion of these studies will provide important new data that could justify support for expanding the clinical development program to include testing in AD patients.